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Functional Instability Allows Access to DNA in Longer Transcription Activator-Like Effector (TALE) Arrays

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Functional Instability Allows Access to DNA in Longer Transcription Activator-Like Effector (TALE) Arrays RESEARCH ARTICLE Functional instability allows access to DNA in longer transcription Activator-Like effector (TALE) arrays Kathryn Geiger-Schuller1,2†, Jaba Mitra3, Taekjip Ha1,2,4,5,6,7,8, Doug Barrick1,2* 1T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States; 2Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United States; 3Materials Science and Engineering, University of Illinois Urbana-Champaign, Urbana, United States; 4Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana Champaign, Urbana, United States; 5Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, United States; 6Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States; 7Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, United States; 8Howard Hughes Medical Institute, Baltimore, United States Abstract Transcription activator-like effectors (TALEs) bind DNA through an array of tandem 34- residue repeats. How TALE repeat domains wrap around DNA, often extending more than 1.5 helical turns, without using external energy is not well understood. Here, we examine the kinetics of DNA binding of TALE arrays with varying numbers of identical repeats. Single molecule fluorescence analysis and deterministic modeling reveal conformational heterogeneity in both the *For correspondence: free- and DNA-bound TALE arrays. Our findings, combined with previously identified partly folded [email protected] states, indicate a TALE instability that is functionally important for DNA binding. For TALEs forming Present address: †Broad less than one superhelical turn around DNA, partly folded states inhibit DNA binding. In contrast, Institute of Harvard and for TALEs forming more than one turn, partly folded states facilitate DNA binding, demonstrating a Massachusetts Institute of mode of ‘functional instability’ that facilitates macromolecular assembly. Increasing repeat number Technology, Cambridge, United slows down interconversion between the various DNA-free and DNA-bound states. States DOI: https://doi.org/10.7554/eLife.38298.001 Competing interest: See page 20 Funding: See page 20 Introduction Received: 11 May 2018 Transcription activator-like effectors (TALEs) are bacterial proteins containing a domain of tandem Accepted: 27 February 2019 DNA-binding repeats as well as a eukaryotic transcriptional activation domain (Kay et al., 2007; Published: 27 February 2019 Ro¨mer et al., 2007). The repeat domain binds double stranded DNA with a register of one repeat per base pair. Specificity is determined by the sequence identity at positions twelve and thirteen in Reviewing editor: Antoine M van Oijen, University of each TALE repeat, which are referred to as repeat variable diresidues (RVDs) (Boch et al., 2009; Wollongong, Australia Miller et al., 2015; Moscou and Bogdanove, 2009). This specificity code has enabled design of TALE-based tools for transcriptional control (Cong et al., 2012; Geissler et al., 2011; Li et al., Copyright Geiger-Schuller et 2012; Mahfouz et al., 2012; Morbitzer et al., 2010; Zhang et al., 2011), DNA modifications al. This article is distributed under (Maeder et al., 2013), in-cell microscopy (Ma et al., 2013; Miyanari et al., 2013), and genome edit- the terms of the Creative Commons Attribution License, ing (TALENs) (Christian et al., 2010; Li et al., 2011). which permits unrestricted use TALE repeat domains wrap around DNA in a continuous superhelix of 11.5 TALE repeats per turn and redistribution provided that (Deng et al., 2012; Mak et al., 2012). Because TALEs contain on average 17.5 repeats (Boch and the original author and source are Bonas, 2010), most form over 1.5 full turns around DNA. Many multisubunit proteins that form rings credited. around DNA require energy in the form of ATP to open or close around DNA (reviewed in Geiger-Schuller et al. eLife 2019;8:e38298. DOI: https://doi.org/10.7554/eLife.38298 1 of 23 Research article Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics eLife digest The DNA contains all the information needed to build an organism. It is made up of two strands that wind around each other like a twisted ladder to form the double helix. The strands consist of sugar and phosphate molecules, which attach to one of for bases. Genes are built from DNA, and contain specific sequences of these bases. Being able to modify DNA by deleting, inserting or changing certain sequences allows researchers to engineer tissues or even organisms for therapeutical and practical applications. One of these gene editing tools is the so-called transcription activator-like effector protein (or TALE for short). TALE proteins are derived from bacteria and are built from simple repeating units that can be linked to form a string-like structure. They have been found to be unstable proteins. To bind to DNA, TALES need to follow the shape of the double helix, adopting a spiral structure, but how exactly TALE proteins thread their way around the DNA is not clear. To investigate this, Geiger-Schuller et al. monitored single TALE units using fluorescent microscopy. This way, they could exactly measure the time it takes for single TALE proteins to bind and release DNA. The results showed that some TALE proteins bind DNA quickly, whereas others do this slowly. Using a computer model to analyze the different speeds of binding suggested that the fast binding comes from partly unfolded proteins that quickly associate with DNA, and that the slow binding comes from rigid, folded TALE proteins, which have a harder time wrapping around DNA. This suggest that the unstable nature of TALEs, helps these proteins to bind to DNA and turn on genes. These findings will help to design future TALE-based gene editing tools and also provide more insight into how large molecules can assemble into complex structures. A next step will be to identify TALE repeats with unstable states and to test TALE gene editing tools that have intentionally placed unstable units. DOI: https://doi.org/10.7554/eLife.38298.002 O’Donnell and Kuriyan, 2006), yet TALEs are capable of wrapping around DNA without energy from nucleotide triphosphate hydrolysis. One possibility is that TALEs bind DNA through an energet- ically accessible open conformation. Consistent with this possibility, we previously demonstrated that TALE arrays can populate partly folded and broken states (Geiger-Schuller and Barrick, 2016). By measuring the length-dependence of protein stability and employing a statistical mechanics Ising model, we previously described several different TALE partly folded states termed ‘end-frayed’, ‘internally unfolded’, and ‘interfacially fractured’ states. Although the calculated populations of partly folded states in TALE repeat arrays are small, they are many orders of magnitude larger than popula- tions of partly folded states in other previously studied repeat arrays (consensus ankyrin [Aksel et al., 2011] and DHR proteins [Geiger-Schuller et al., 2018]) suggesting a potential func- tional role for the high populations of partially folded states in TALE repeat arrays. Consensus TALEs (cTALEs) are designed homopolymeric arrays composed of the most commonly observed residue at each of the 34 positions of the repeat (Geiger-Schuller and Barrick, 2016). In addition to simplifying analysis of folding and conformational heterogeneity in this study, the con- sensus approach simplifies analysis of DNA binding, eliminating contributions from sequence hetero- geneity and providing an easy means of site-specific labeling. Here we characterize DNA binding kinetics of cTALEs using total internal reflection fluorescence single-molecule microscopy. We find that consensus TALE arrays bind to DNA reversibly, with high affinity. Analysis of the dwell-times of the on- and off-states reveals multiphasic binding and unbind- ing kinetics, suggesting conformational heterogeneity in both the free and DNA bound state. We develop a deterministic optimization analysis that supports such a model, and provides rate con- stants for conformational changes in the unbound and bound states, and rate constants for binding and dissociation. Comparing the dynamics observed here to previously characterized local unfolding suggests that locally unfolded states inhibit binding of short cTALE arrays (less than one full superhe- lical turn around DNA), whereas they promote binding of long arrays (more than one full superhelical turn). Whereas local folding of transcription factors upon DNA binding is well documented (Spolar and Record, 1994), local unfolding in the binding process is not. Our results present a new Geiger-Schuller et al. eLife 2019;8:e38298. DOI: https://doi.org/10.7554/eLife.38298 2 of 23 Research article Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics mode of transcription factor binding where the major conformer in the unbound state is fully folded, requiring partial unfolding prior to binding. The critical role of such high energy partly folded states is an exciting example of ‘functional instability’, in which formation of a functional complex is impeded by the fully folded native state, and is instead facilitated by partial disruption of native structure. Results cTALE design Consensus TALE (cTALE) repeat sequence design was described previously (Geiger-Schuller and Barrick, 2016). To avoid self- association of cTALE arrays, we fused arrays to a conserved N-terminal
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